MicroRNAs (miRNAs) are a class of small non-coding regulatory RNAs. Abnormalities in miRNA expression and miRNA-mediated gene regulation have been observed in a variety of human diseases, including psychiatric and neurodevelopmental disorders. In most cases, miRNAs appear to be components of both the genetic architecture of these complex phenotypes and integral parts of the biological pathways that mediate the effects of the primary genetic deficits and could serve as novel therapeutic targets. Some of the strongest evidence for a direct pathogenic link between psychiatric disorders, cognitive dysfunction and miRNAs is provided by studies on the mouse model of a well- established genetic risk factor, the 22q11.2 microdeletion (Df(16)A+/- mice). Analysis of this mouse model provided compelling evidence that the 22q11.2 microdeletion results in abnormal processing of brain miRNAs. Our recent work has identified two major components of the 22q11.2-associated miRNA dysregulation, as well as a major downstream target of the miRNA dysregulation. Despite substantial progress, the extent to which miRNA dysregulation contributes to the cellular, synaptic and behavioral phenotypes associated with the 22q11.2 microdeletion in vivo remains to be determined and additional key downstream targets remain to be identified. This is the focus of this grant proposal. Understanding how miRNA-dependent gene regulation disrupted by a structural mutation with unequivocal causal links to schizophrenia and cognitive dysfunction contributes to the emergence of the psychiatric and cognitive phenotypes associated with this genomic imbalance will provide important mechanistic insights and can guide analysis of miRNA contribution to other psychiatric, neurodevelopmental and cognitive disorders. PUBLIC HEALTH RELEVANCE: This proposal is inherently translational in nature, aimed at elucidating the neurobiological substrates of psychiatric disease. It is aimed at identifying specific patterns of abnormal gene expression caused by loci predisposing to schizophrenia and cognitive dysfunction and link them to the cellular, synaptic and cognitive processes they impact. Identifying such patterns would set the stage for a novel approach to therapies aimed at reversing the underlying pathophysiology and restoring normal function.